Nine neurodegenerative diseases are caused by expansions of polyglutamine tracts. Among these disorders is Kennedy's disease, a motor neuronopathy caused by a mutation in the androgen receptor gene. It is not well understood how this mutation causes neuronal degeneration. Lack of Such knowledge is an important problem because it hinders the development of treatment strategies. The laboratory's long-range goal is to understand the pathogenetic mechanisms by which expansions of polyglutamine tracts cause neuronal dysfunction and death. The objective of this application is to determine the molecular basis for the alteration in function that the receptor undergoes as a result of polyglutamine expansion. The central hypothesis is that the mutation alters normal androgen receptor function by affecting acetylation and phosphorylation cascades, and by conferring a toxic gain-of-function that leads to oxidative injury. The rationale for these studies is that understanding the molecular pathways altered by the mutation will yield insights into mechanisms of neurodegeneration, thereby suggesting novel therapeutic targets. The central hypothesis will be tested by pursuing the following two specific aims: 1) Identify the molecular pathways that are dysregulated by the expanded polyglutamine androgen receptor, 2) Establish which of these dysregulated pathways is causally related to cell dysfunction and death. The experimental approach will be to characterize altered androgen receptor function, to modify the activity of acetylation and phosphorylation cascades, and to evaluate the role of iron mediated oxidative injury in cell dysfunction and death. It is my expectation that this award will provide significant protected time to foster my career development as a neuroscientist, and that this scientific approach will yield important data that will serve as the basis for an R01 grant application in years 4 and 5 of this award. We also expect to identify important pathways dysregulated as a result of expanded polyglutamine tracts, and to determine which of these dysregulated pathways contributes to cell dysfunction and death. Such outcomes will have general impact because this new knowledge will suggest novel targets for the treatment of this and related diseases.